Atypical Rasmussen's Encephalitis

A three-year-old female patient was admitted to our institution due to subacute fever, intermittent vomiting, persistent bilateral mydriasis after cycloplegia, right central facial palsy, and mild right hemiparesis with hyperreflexia. Brain MRI shows encephalitis in frontal, parietal, insular, and left putamen course and loss of cortical volume and white matter of the entire left hemisphere which are features described in Rasmussen's encephalitis (RE). Therapy with intravenous methylprednisolone bolus was initiated, with adequate clinical response. We consider in this case the diagnosis of atypical RE by imaging criteria in the subacute stage. There are few reports of atypical RE without epilepsy or continuous partial epilepsy. Our purpose is to present a case of a patient with RE images without epilepsy seizures and review the diagnostic and therapeutic approach of RE.


Introduction
Rasmussen's encephalitis (RE) is a rare progressive neurologic disorder characterized by unilateral atrophy of the cerebral cortex, refractory focal seizures, progressive hemiparesis, and cognitive deficit.Neuropathological studies have demonstrated the theory of a T-cell response to one or more antigenic epitopes that mediate the onset of brain damage, which may be a window of treatment for future therapies [1].RE is a chronic and progressive disorder, with refractory focal seizures and even though continuous partial epilepsy, progressive unilateral motor function impairment, and cognitive compromise.The estimated annual incidence is 1.7 cases per 10 million people under 16 years of age, it is more frequent in children between 6 and 8 years of age, but it can also affect adolescents and adults, it has not been identified any relation with sex, geographical area, or ethnic group [1,2].RE, defined as an immune-mediated disease, with the constant involvement of T cells and histopathological findings of inflammation in cortical multifocal areas, associated with perineuronal lymphocytic infiltration, T cells (which are fundamental in brain damage) and microglial activation [3].Subsequently, CD8+ T cytotoxic cells generate the activation of the inflammation pathway [4].and, therefore, the release of IL-1, and the release of granzymes, responsible for neuronal apoptosis [4], CD4+ T-cell clones and γδ T cells secreting IFN-γ, TNF, and cytokines activation are also involved [5,6].The diagnosis of RE is based on clinical, electrophysiological, and morphological characteristics [1].
The European consensus developed in 2005 by a panel of experts proposed the RE diagnostic criteria which are still accepted and used today.The criteria in the Part A are typical of the first cases including: i. Clinical Focal epilepsy with or without CPE and unilateral cortical deficit, ii.EEG with unihemispheric slowing with or without epileptiform activity and onset of unilateral seizures, and iii.MRI with unihemispheric focal cortical atrophy and at least one of the following: hyperintensity signal of gray or white matter T2/FLAIR w/o hyperintensity signal or atrophy of caudate head ipsilateral [1,2].If the patient does not meet the Part A criteria, the two of the three criteria of the part B should be met, which are likely to cover early cases and less common presentations including i. Clinical characteristics of continuous partial epilepsy (CPE) or progressive unilateral cortical deficit, ii.Progressive unihemispheric focal cortical atrophy, and iii.Histopathological features of T-cell-dominated encephalitis with activated microglial cells typically, but not necessarily forming nodules and relative astrogliosis; numerous parenchymal macrophages, B cells or plasma cells or viral inclusion bodies exclude the diagnosis of Rasmussen's encephalitis [1,2].

Case Presentation
We present the case of a previously healthy 3-year-old female patient, initially brought to the ophthalmologist in April of 2023 for right eye strabismus, the indication was occlusion patch and follow up.In June of 2023, the patient presented intermittent strabismus and fundus examination described normal but for persistent mydriasis after application of cycloplegic eye drops the patient is transferred to the ambulatory Pediatric Neurology service in June of 2023.At the time of the consultation patient also had vomiting, asthenia and abnormal speech, on the clinical examination reported convergent strabismus of the left eye with bilaterally non-reactive mydriatic 4 mm pupils and ordered neuroimages.A first brain MRI done on June 12 of 2023 (Figures 1, 2) was reported with increased depth of cortical sulci of the left cerebral hemisphere on frontal, parietal, temporal and insular with gliosis and atrophy of the cortex, without defining signs of ischemic involvement in vascular territory or acute inflammatory.

FIGURE 1: First Brain MRI Axial T2 FIGURE 2: First brain MRI Coronal
Given the brain imagenologic findings, it was suspected meningoencephalitis inflammatory process, the patient was referred on June 15 of 2023 to the emergency room of our institution for evaluation.At admission, the patient presented fever up to 38.5ºC, facial asymmetry and vomiting, on the clinical examination patient was alert, with no meningeal signs, language normal, bilateral mydriasis, strabismus, right facial palsy, and mild right hemiparesis and hyperreflexia.Enquiring the parents about other symptoms presented by the patient, they referred patient had intermittent fever and vomiting during two months previous to the admission.Four days before arriving to our hospital the patient presents persistent fever, facial asymmetry, asthenia, hyporexia, and vomiting n° three a day.Patient had brought the patient to another institution for the facial asymmetry where the diagnosis was peripheral facial palsy and the mentioned MRI features were considered a previous not related feature, and patient was discharged with oral prednisolone.
Patient was born at 40 weeks by cesarean section, from the first normal gestation of healthy parents, indication of cesarean section was cord wrapped around baby neck leading to unsatisfactory fetal status.Spontaneous neonatal adaptation, adequate weight, and height at birth.Family history of epilepsy of uncle, grandfather, and 2 cousins.Motor and language developmental skills were normal.After the admission in our institution, the patient underwent to brain images studies, la to extend diagnostic studies, including contrasted brain and orbit MRI studies were performed on June 15 of 2023 (Figures 3, 4, 5), the report was asymmetric decrease of the cortical volume of the left cerebral hemisphere.Angioresonance with arterial and venous phases was normal (Figures 6, 7, 8) and the brain spectroscopy (Figures 9, 10) showed reduction of choline and creatine peaks consistent with gliosis.MRI of the orbits for optic nerve study was normal.A 12-hour videoelectroencephalogram record of the patient was normal in particular without seizure events or electrographic epileptic abnormalities (Figure 11).A 12 hours videoelectroencephalograpy (Figure 12) was done, no seizures and no epileptic abnormalities were observed.

FIGURE 11: EEG
The electroencephalographic record was normal

TABLE 1: Laboratory results
With the diagnosis of atypical presentation of RE as the first possibility, the treatment initiated was corticosteroids with intravenous bolus of intravenous methylprednisolone, without adverse effects.The patient had no seizures or abnormal movements during the hospitalization.Patient evolved satisfactorily, fever stopped, the patient remained stable without epileptic seizures symptoms and without major functional or cognitive impairment, and the persistent cycloplegic mydriasis observed at the admission was resolved and interpreted as a prolonged pharmacologic effect.At the discharge, oral corticosteroids were indicated at the discharge and multidisciplinary and brain MRI follow-up.

Discussion
The present clinical case corresponds to an atypical presentation of RE since no clinical signs suggestive of epileptic seizures have been documented until the patient discharge, correlated with the normal 12 hours videoelectroencephalogram traced of the patient who did not present seizure or ictal event along the register, despite epileptiform abnormalities on EEG are common in ER, and often develop into electrographic seizures, continuous partial epilepsy is not always accompanied by recognizable ictal surface activity.[5].Particularly, our patient presented general symptoms as asthenia, and fever that has been described in patients with RE [7].However, the main feature on the MRI could be explained by RE with an asymmetric decrease in the volume of the cortex of the left cerebral hemisphere, with increased involvement of the frontal, parietal, temporal and insular lobes, gliosis in early stage given by hypersignal in FLAIR sequence in the insula and left putamen.
Brain MRI arises as very useful diagnostic and follow-up imagenologic study in ER.It has been described in the acute stage, unilateral enlargement of the ventricular system, in T2 and FLAIR hyperintensity is observed at the cortical or subcortical level, being the perisylvian region the site of predilection for signal change and volume loss, additionally, ipsilateral cortical atrophy of the head of the caudate nucleus accompanying hemispheric atrophy is usually an early sign [6,8].Other studies should be performed in RE, such studies on CSF and blood exclude infections of the central nervous system or other associated disorders.To our knowledge there are no specific biochemical biomarkers for RE, but there are studies that have detected different viral particles among which is the herpes virus, however patient with Film array of meningitis and Ac IgG and IgM Herpes negative.CSF analysis was normal.
Clinical course of RE presents three stages: the first stage is the "prodromal stage", an average duration of 7.1 months, characterized by nonspecific and infrequent seizures associated with mild hemiparesis.Subsequent months all patients experience the second stage the "acute stage" which is based on focal motor seizures or continuous partial epilepsy (CPE) characterized by being an intractable focal somatomotor status epilepticus, continuous focal spasms of a part of the body (distal limb or face) and with cortical origin; This stage has an average duration of 25 months.The last stage is the "residual stage" characterized by less frequent epileptic seizures and persistent and stable neurological deficits [1].
Further, it is necessary to follow closely our patient to detect clinical manifestations such as late seizures or abnormal movements, but we expect that inflammatory immune-mediate process of RE becomes controlled.However, ER patients without or with delayed seizure onset have been published.There are four reports of atypical RE patients without seizures or delayed seizures onset [9][10][11][12].In a retrospective study of ten patients with atypical RE, the most frequent feature was progressive hemiparesis without seizure or late-onset events, followed by dyskinetic movements, late-onset seizures associated with unilateral caudate atrophy, image mimicking focal cortical dysplasia as the first MRI abnormality, and cluster epileptic spasms, only one patient remained without seizures [11].Two reports of RE patients which did not present seizures (Table 2) [13,14], in one report the patient had dual epileptogenic pathologic conditions, cortical dysplasia and RE [13], and in the other report the patient presented relapsing-remitting bilateral RE without seizures [14].Currently, anticonvulsant medications, immunotherapy and surgery are the three fundamental pillars in the treatment of RE.Based on the neuroinflammatory pathological basis of RE, immunomodulatory therapy including high dose of corticosteroids as first line treatment, intravenous immunoglobulins, plasmapheresis, rituximab, and oral immunosuppressor medications as azathioprine and tacrolimus [2,15,16].Early immunomodulatory therapy has benefits such as inhibiting seizure episodes, preserving neurological function, and delaying the requirement for surgery, however it can potentially be associated with loss of functions represented by the affected hemisphere.However, anticonvulsant medications alone or in combination have a limited effect on ER [17].Hemispherectomy is considered as a definite surgical treatment for intractable focal epilepsy in RE but the timing of surgery for better cognitive outcome is controversial.Disconnective hemispherectomy reduces the risk of hydrocephalus and shunting compared

FIGURE 3 :
FIGURE 3: Second Brain MRI, with contrast.Decrease of left hemisphere volume.Note that frontal, parietal and temporal lobes are the most affected as observed in the first MRI.

FIGURE 4 :
FIGURE 4: Second Brain MRI with contrast axial section.Non enhancement observed on left hemisphere

FIGURE 5 :
FIGURE 5: Second brain MRI, contrasted study, coronal section This figure details marked compromise of the insular region of left hemisphere also observed in the first brain MRI of the patient.

Figure 6 , 7
Figure 6, 7 show a normal patient`s Angioresonance.Without defined alteration in the caliber of the arterial or venous vascular structures, no occlusion of the left middle cerebral artery or the left intracranial internal carotid artery was observed.

FIGURE 9 :FIGURE 10 :
FIGURE 9: Normal brain MR spectroscopy of the right hemisphere

Table 1 ,
underwent to lumbar puncture obtaining clear and colorless CSF, normal CSF cytochemistry, ADA, normal serum and CSF lactate values; and negative film array and cultures for pathogens in CSF discarding concomitant infection of central nervous system.

TABLE 2 : Reports of atypical pediatric presentations of RE with delayed seizures and or without seizures
a Dual pathology (cortical dysplasia) b Bilateral relapsing-remitting RE